Our overall objective is to elucidate factors that regulate blood lipid levels and that lead to the development of hypertriglyceridemia and atherosclerosis, a major vascular complication of diabetes mellitus. Through the understanding of these factors, we would hope to learn how to prevent and reverse hypertriglyceridemia and vascular complications that develop as a result of particular dietary patterns and of hormonal imbalances. We shall focus our attention on the hypersecretion of very low density lipoproteins by the liver's Golgi apparatus in insulin-resistant, hyperinsulinemic experimental diabetes using animals in which hyperlipemia seems to result from over-production of lipoproteins by the liver under the influence of dietary carbohydrate an insulin. Radioactive precursors of very low density lipoproteins, such as glycerol, free fatty acids and dietary glucose and fructose will be injected or fed to rats and mice (control, insulin-treated alloxan diabetic, and to obese-hyperglycemic, hyperinsulinemic mice (ob/ob) and rats (Zucker). Incorporation into radioactive triglycerides in various intracellular compartments of the liver will be followed as a function of time; in the same experiments radioactivity in triglycerides will be measured as they appear and desappear from the circulation as very low density lipoproteins. Data will be analyzed by multicompartmental analysis. Particular attention will be paid to the kinetic analysis of lipogenic rates (de novo fatty acid synthesis from various precursors, hepatic triglyceride synthesis, and lipoprotein-triglyceride synthesis), rates of nascent lipoprotein synthesis and secretion, and intracellular triglyceride (fat droplet) formation accumulation, and lipolysis as influenced by diabetes, insulin, and diet. Data will be analyzed by multicomparmental analysis. Based upon the results of these analyses, hypotheses will be formulated and tested in cell-free systems in an attempt to elucidate the biochemical mechanisms involved in the regulation of hepatic lipoprotein secretion by insulin and dietary carbohydrates.